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Class of 2010 Abstract / OBJECTIVES: To comprehensively review medical literature and report angiotension converting enzyme inhibitors (ACE-­‐I) adverse drug reactions including, incidences, mechanism of action, predisposing conditions, and report prevention and treatments. METHODS: This was a descriptive retrospective study of data related to ACE-­‐I adverse drug reactions other than ACE-­‐I induced cough. It was to review the ADR that accompany with the use of ACE-­‐I. Literature obtained through search engines MEDLINE and OVID SP available through the Arizona Health and Science Library at the University of Arizona. RESULTS: This comprehensive literature review looked at angioneurotic edema, orthostatic hypotension, hyperkalemia, and increased risk of bleeding and anaphylaxis with tPA and to a minor extent Elevated serum creatinine, and Teratogenicity. Angioneurotic edema (angioedema) reports initially estimated an incidence of 0.1 to 0.7%. A comprehensive review suggested the incidence was even lower at 0.1 to 0.2%, but the OCTAVE trial that specifically looked at angioedema as an endpoint estimated an incidence of ~0.7% although the study only had a 24-­‐week follow up. Most patients that discontinued treatment due to angioedema experienced symptom relief within 72 hours. The incidence of orthostatic hypotension from a study that followed patients on lisinopril was only 0.25%;moreover, a meta-­‐analysis by Agusti et al included 51 RCT that reported a relative risk of developing OH on an ACE-­‐I alone was 1.95. Hyperkalemia incidence reporeted varied from 1.1% to 10%; the more recent literature suggests a value near the lower end of this range. Elevated serum creatinine appears to occur early in ACE-­‐I treatment with discontinuation resolving in resolution. ACE-­‐I have been shown to be teratogenic during any trimester and should generally be avoided in pregnancy. There appears to be an increased risk of bleeding and anaphylactoid typer reactions when alteplase and ACE-­‐I are used simultaneously. Muravyov et al reported the viscosity of whole blood and plasma to be decreased after only three weeks of ACE-­‐I administration. CONCLUSIONS: With the continued increasing use of ACE-­‐Is and the drug class' ability to achieve therapeutic outcomes in a wide array of patient populations, it is important to better understand the processes and mechanisms behind the ADRs associated with ACE-­‐I therapy. A basic understanding of incidence rates and physiologic mechanisms will allow clinicians to properly assess the probability of causation and better treat patients who have experienced an ACE-­‐I induced ADR. However, an in-­‐depth level of understanding can help guide clinicians in making decisions that will hopefully decrease the amount of ADRs their patients experience or prevent their patients from developing ACE-­‐I related ADR altogether. It is important to note that, in most of the aforementioned ADR situations, treatment consists of ACE-­‐I discontinuation and avoidance of future exposures.

by Patricia Jane Anderson. / Thesis (M. Phil.)--Chinese University of Hong Kong, 1993. / Includes bibliographical references (leaves 199-215). / List of Figures --- p.i / List of Tables --- p.v / List of Abbreviations --- p.viii / Abstract --- p.1 / Introduction --- p.3 / Chapter Chapter 1 - --- Literature Reviews / Chapter 1.1 --- Pharmacoanthropology and Pharmacogenetics --- p.5 / Chapter 1.1.1 --- Genetic Polymorphisms --- p.7 / Chapter 1.1.2 --- Pharmacogenetics in Asians and Caucasians --- p.13 / Chapter 1.1.2.1 --- ACE-inhibitors in Asians and Caucasians --- p.18 / Chapter 1.2 --- The Renin Angiotensin System --- p.20 / Chapter 1.2.1 --- Discovery of Inhibitors of Angiotensin Converting Enzyme --- p.24 / Chapter 1.3 --- ACE-Inhibiting Drugs --- p.25 / Chapter 1.3.1 --- Pharmacokinetics and Pharmacodynamics of Perindopril --- p.28 / Chapter 1.3.2 --- The Pharmacokinetics and Pharmacodynamics of Cilazapril --- p.32 / Chapter Chapter 2 - --- General Methodology / Chapter 2.1 --- Introduction --- p.38 / Chapter 2.2 --- Subjects --- p.49 / Chapter 2.3 --- Sample Collection --- p.40 / Chapter 2.3.1 --- Blood Samples --- p.40 / Chapter 2.3.2 --- Urine Samples --- p.40 / Chapter 2.4 --- Blood Pressure and Heart Rate Measurements --- p.41 / Chapter 2.5 --- Measurement of Transthoracic Electrical Bioimpedance --- p.41 / Chapter 2.5.1 --- Background --- p.42 / Chapter 2.5.2 --- Practical Details --- p.45 / Chapter 2.6 --- Data Analysis --- p.48 / Chapter 2.6.1. --- Analysis of Pharmacokinetic Parameters --- p.48 / Chapter 2.6.2 --- Analysis of Pharmacodynamic Parameters --- p.59 / Chapter 2.6.3 --- Analysis of Non-Invasive Haemodynamic Monitoring Data --- p.60 / Chapter 2.7 --- Statistical Analysis --- p.64 / Chapter Chapter 3 - --- The Perindopril Study / Chapter 3.1 --- Introduction --- p.67 / Chapter 3.1.1 --- Aims --- p.67 / Chapter 3.2 --- Methodology --- p.68 / Chapter 3.2.1 --- Inclusion Criteria --- p.68 / Chapter 3.2.2 --- Non-Inclusion Criteria --- p.69 / Chapter 3.2.3 --- Study Design --- p.69 / Chapter 3.2.4 --- Blood Sampling --- p.71 / Chapter 3.2.5 --- Urine Sampling --- p.71 / Chapter 3.2.6 --- Blood Pressure and Heart Rate --- p.72 / Chapter 3.2.7 --- Non-invasive Haemodynamic Monitoring --- p.72 / Chapter 3.2.8 --- Analysis of Plasma Samples --- p.73 / Chapter 3.2.9 --- Hormone and Enzyme Assays --- p.74 / Chapter 3.3 --- Data Analysis and Statistical Methods --- p.75 / Chapter 3.3.1 --- Pharmacokinetic Analysis of Plasma --- p.75 / Chapter 3.3.2 --- Pharmacokinetic Analysis of Urine --- p.75 / Chapter 3.3.3 --- Pharmacodynamic Analysis of Hormone Data --- p.75 / Chapter 3.3.4 --- Analysis of Haemodynamic Monitoring Data --- p.76 / Chapter 3.3.5 --- Statistical Analysis --- p.76 / Chapter 3.4 --- Pharmacokinetic Results --- p.77 / Chapter 3.4.1 --- Pharmacokinetics of Perindopril in Plasma --- p.77 / Chapter 3.4.2 --- Pharmacokinetics of Perindopril in Urine --- p.84 / Chapter 3.4.3. --- Pharmacokinetics of Perindoprilat in Plasma --- p.85 / Chapter 3.4.4 --- Pharmacokinetics of Perindoprilat in Urine --- p.89 / Chapter 3.5 --- Pharmacodynamic Results --- p.89 / Chapter 3.5.1 --- Angiotensin Converting Enzyme Inhibition --- p.89 / Chapter 3.5.2 --- Angiotensin I (AI) --- p.102 / Chapter 3.5.3 --- Aldosterone and Plasma Renin Activity (PRA) --- p.102 / Chapter 3.5.4 --- Plasma Protein Binding --- p.102 / Chapter 3.5.5 --- Blood Pressure and Heart Rate --- p.107 / Chapter 3.5.6. --- Safety and Tolerance --- p.108 / Chapter 3.5.7 --- Non-invasive Haemodynamic Monitoring --- p.108 / Chapter 3.6 --- Discussion --- p.120 / Chapter Chapter 4 - --- The Cilazapril Study / Chapter 4.1 --- Introduction --- p.135 / Chapter 4.1.1 --- Aims --- p.135 / Chapter 4.2 --- Methodology --- p.136 / Chapter 4.2.1 --- Inclusion Criteria --- p.136 / Chapter 4.2.2. --- Exclusion Criteria --- p.136 / Chapter 4.2.3 --- Study Design --- p.137 / Chapter 4.2.4 --- Blood Sampling --- p.139 / Chapter 4.2.5 --- Urine Sampling --- p.140 / Chapter 4.2.6 --- Blood Pressure and Heart Rate --- p.140 / Chapter 4.2.7 --- Non-Invasive Haemodynamic Monitoring --- p.140 / Chapter 4.2.8 --- Analysis of Plasma Cilazaprilat Samples --- p.142 / Chapter 4.2.9 --- Hormone and Enzyme Assays --- p.143 / Chapter 4.3 --- Data Analysis and Statistical Methods --- p.143 / Chapter 4.3.1 --- Pharmacokinetic Analysis --- p.143 / Chapter 4.3.2 --- Pharmacodynamic Analysis of Hormone Data --- p.144 / Chapter 4.3.3 --- Analysis of Non-Invasive Haemodynamic Monitoring Data --- p.144 / Chapter 4.3.4 --- Statistical Analysis --- p.146 / Chapter 4.4 --- Pharmacokinetic Results --- p.146 / Chapter 4.4.1 --- Pharmacokinetics of Cilazaprilat in Plasma --- p.146 / Chapter 4.5 --- Pharmacodynamic Results --- p.150 / Chapter 4.5.1 --- Angiotensin Converting Enzyme Inhibition --- p.150 / Chapter 4.5.2 --- Aldosterone and Plasma Renin Activity (PRA) --- p.155 / Chapter 4.5.3 --- Blood Pressure and Heart Rate --- p.155 / Chapter 4.5.4 --- Safety and Tolerance --- p.159 / Chapter 4.5.5 --- Non-Invasive Haemodynamic Monitoring --- p.160 / Chapter 4.6 --- Discussion --- p.182 / Chapter Chapter 5 - --- General Discussion --- p.188 / Appendix --- p.195 / References --- p.199 / Acknowledgements --- p.216

Thesis (M. Phil.)--University of Hong Kong, 2001. / Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 2007. / Also available in print.

Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliographical references.

Thesis (M. Med. Sc.)--University of Hong Kong, 2006.

The renin-angiotensin system plays a central role in the maintenance of blood pressure. Angiotensin II, the main effector of this system, results from the action of angiotensin-converting enzyme (ACE) on angiotensin I. Angiotensin II, maintains vasomotor tone via its vasoconstrictor action, and also increases salt and water retention by stimulating the release of aldosterone. ACE inhibitors, such as captopril, enalapril and lisinopril, are highly effective in the treatment of hypertension and congestive cardiac failure. Previous studies have suggested that angiotensin converting enzyme (ACE) production may be enhanced during pharmacological inhibition of the enzyme. Little is known, however about the mechanism of this induction. After demonstrating increases in circulating ACE protein in cardiac failure patients receiving the ACE inhibitor captopril, a rat model was used to study this effect. A sensitive enzyme linked immunosorbent assay for rat ACE was developed and a partial cDNA for rat ACE cloned to enable examination of ACE mRNA and protein expression during enzyme inhibition with enalapril. Rat lung ACE mRNA increased by 156% (p<0.05) and ACE protein doubled within 3 hours of administering a single dose of enalapril. Testicular ACE mRNA also increased by 300% (p<0.05) within 2 hours and returned to pretreatment levels by 6 hours. The angiotensin II antagonist saralasin similarly caused a significant (p<0.0001) 800% enhancement of mRNA expression. Aldosterone pretreatment of rats prior to enalapril administration was found to abolish this mRNA induction. These findings indicate that increased ACE expression during inhibition results from reduced levels of angiotensin II with consequent reduced stimulation of the angiotensin 11 receptor and its effects, such as aldosterone release. This suggests that ACE levels are regulated by a negative feedback loop involving the distal components of the renin-angiotensin system, namely angiotensin II and aldosterone. In situ hybridisation and immunohistochemical techniques were employed to localise the site of this inductive response in rat tissue sections. It was found that lung macrophages were markedly induced to produce ACE, as was ACE in seminiferous tubules. ACE induction was also noted in the expected sites of renal tubular epithelium and glomerular tissue. Interestingly, ACE expression was also enhanced in cardiac valves. In these studies it has been conclusively demonstrated that new ACE expression is induced by enzyme inhibitor therapy. A variety of techniques have been developed that will allow futher study of ACE in rat tissues.

published_or_final_version / abstract / Biological Sciences / Master / Master of Philosophy

Thesis (M.S. in food science)--Washington State University, December 2007. / Includes bibliographical references.